In:
Neuropathology and Applied Neurobiology, Wiley
Kurzfassung:
Mesial Temporal Lobe Epilepsy‐associated Hippocampal Sclerosis (MTLE‐HS) is a syndrome associated with various aetiologies. We previously identified CD34‐positive extravascular stellate cells (CD34+ cells) possibly related to BRAF V600E oncogenic variant in a subset of MTLE‐HS. We aimed to identify the BRAF V600E oncogenic variants and characterise the CD34+ cells. Methods We analysed BRAF V600E oncogenic variant by digital droplet Polymerase Chain Reaction in 53 MTLE‐HS samples (25 with CD34+ cells) and 9 non‐expansive neocortical lesions resected during epilepsy surgery (5 with CD34+ cells). Ex vivo multi‐electrode array recording, immunolabelling, methylation microarray and single nuclei RNAseq were performed on BRAF wildtype MTLE‐HS and BRAF V600E mutant non‐expansive lesion of hippocampus and/or neocortex. Results We identified a BRAF V600E oncogenic variant in 5 MTLE‐HS samples with CD34+ cells (19%) and in 5 neocortical samples with CD34+ cells (100%). Single nuclei RNAseq of resected samples revealed two unique clusters of abnormal cells (including CD34+ cells) associated with senescence and oligodendrocyte development in both hippocampal and neocortical BRAF V600E mutant samples. The co‐expression of the oncogene‐induced senescence marker p16 INK4A and the outer subventricular zone radial glia progenitor marker HOPX in CD34+ cells was confirmed by multiplex immunostaining. Pseudotime analysis showed that abnormal cells share a common lineage from progenitors to myelinating oligodendrocytes. Epilepsy surgery led to seizure freedom in 8 of the 10 patients with BRAF mutant lesions. Interpretation BRAF V600E underlies a subset of MTLE‐HS and epileptogenic non‐expansive neocortical focal lesions. Detection of the oncogenic variant may help diagnosis and opens perspectives for targeted therapies.
Materialart:
Online-Ressource
ISSN:
0305-1846
,
1365-2990
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2023
ZDB Id:
2008293-9
